Notch1 cortical signaling regulates epithelial architecture and cell-cell adhesion.

Notch receptors control tissue morphogenic processes that involve coordinated changes in cell architecture and gene expression, but how a single receptor can produce these diverse biological outputs is unclear. Here, we employ a 3D model of a human ductal epithelium to reveal tissue morphogenic defects result from loss of Notch1, but not Notch1 transcriptional signaling. Instead, defects in duct morphogenesis are driven by dysregulated epithelial cell architecture and mitogenic signaling which result from the loss of a transcription-independent, Notch1 cortical signaling mechanism that ultimately functions to stabilize adherens junctions and cortical actin. We identify that Notch1 localization and cortical signaling are tied to apical-basal cell restructuring and discover that a Notch1-FAM83H interaction underlies control of epithelial adherens junctions and cortical actin. Together, these results offer new insights into Notch1 signaling and regulation and advance a paradigm in which transcriptional and cell adhesive programs might be coordinated by a single receptor.

Effect of Bicortical Interfragmentary Screw Size on the Fixation of Metacarpal Shaft Fractures: A 3-Dimensional-Printed Biomechanical Study.

Purpose: Spiral metacarpal fractures fixed with 2 non-lagged, interfragmentary cortical screws were tested to failure. The effect of screw size (1.2 mm, 1.5 mm, 2.0 mm, and 2.3 mm) on construct strength was tested in 3-point bending. Methods: Three-dimensional-printed metacarpal test models were reproduced from computed tomography scans to reduce the confounding variables of bone density and anatomy, often encountered when using cadavers. Results: No significant difference was found between the screw sizes, and the peak failure force was similar. Drill bit fracture and deformation during the insertion of the smallest screw (1.2 mm) as well as model failure during the insertion of the largest screw (2.3 mm) were found in some cases. Conclusions: Screws of 1.5 mm and 2.0 mm in diameter were of sufficient strength and did not have the issues encountered with smaller or larger screws. Concerns from previous authors regarding intraoperative fracture were consistent with the pre-testing failure of some 2.3-mm models. Clinical Relevance: Screws of 1.5 mm or 2 mm appear adequate for the fixation of spiral fracture patterns in metacarpal shafts using bicortical non-lagged technique with a low risk of fixation complications.

Functional Significance of CD57 Expression on Human NK Cells and Relevance to Disease.

Historically, human NK cells have been identified as CD3(-)CD56(+)CD16(±) lymphocytes. More recently it has been established that CD57 expression defines functionally discrete sub-populations of NK cells. On T cells, CD57 expression has been regarded as a marker of terminal differentiation and (perhaps wrongly) of anergy and senescence. Similarly, CD57 expression seems to identify the final stages of peripheral NK cell maturation; its expression increases with age and is associated with chronic infections, particularly human cytomegalovirus infection. However, CD57(+) NK cells are highly cytotoxic and their presence seems to be beneficial in a number of non-communicable diseases. The purpose of this article is to review our current understanding of CD57 expression as a marker of NK cell function and disease prognosis, as well as to outline areas for further research.

Courvoisier's gallbladder: law or sign?

BACKGROUND: Variously described as Courvoisier's law, sign, or even gallbladder, this eponymous "law" has been taught to medical students since the publication of Courvoisier's treatise in 1890. METHODS: We reviewed Courvoisier's original "law," the modern misconceptions surrounding it, and the contemporary evidence supporting and explaining his observations. RESULTS: Courvoisier never stated a "law" in the context of a jaundiced patient with a palpable gallbladder. He described 187 cases of common bile duct obstruction, observing that gallbladder dilatation seldom occurred with stone obstruction of the bile duct. The classic explanation for Courvoisier's finding is based on the underlying pathologic process. With the presence of gallstones come repeated episodes of infection and subsequent fibrosis of the gallbladder. In the event that a gallstone causes the obstruction, the gallbladder is shrunken owing to fibrosis and is unlikely to be distensible and, hence, palpable. With other causes of obstruction, the gallbladder distends as a result of the back-pressure from obstructed bile flow. However, recent experiments show that gallbladders are equally distensible in vitro, irrespective of the pathology, suggesting that chronicity of the obstruction is the key. Chronically elevated intraductal pressures are more likely to develop with malignant obstruction owing to the progressive nature of the disease. Gallstones cause obstruction in an intermittent fashion, which is generally not consistent enough to produce such a chronic rise in pressure. CONCLUSION: We hope that reminding clinicians of Courvoisier's actual observations will reestablish the usefulness of this clinical sign in the way he intended.